Abstract Universal influenza vaccines should be possible if conserved antigens of influenza are effectively targeted and effective antiviral immune responses are generated against those antigens. DNA vaccination is an appealing approach for delivering universal influenza vaccines, however, natural immune responses to conserved influenza antigens are typically weak and most DNA vaccines tested in humans have not elicited robust humoral immunity. To overcome the obstacles to developing universal influenza DNA vaccines, we are using novel composite immunogens and delivering them with a next generation Gene Gun device that combines several engineering and formulation innovations that increase immunogenicity by increasing the number of skin cells and antigen presenting cells expressing vaccine antigen. We have already obtained encouraging results with a universal influenza A (UFluA) DNA vaccine. Under this SBIR proposal, we intend to test a companion universal influenza B (UFluB) DNA vaccine to create a more comprehensive universal A/B vaccine (UFluA/B) that will provide broad protective coverage from all influenza A and B types capable of infecting humans. If we are successful at demonstrating that a single UFluA/B DNA vaccine can induce broad responses and protection in mice in the phase I effort, we will advance this this product to preclinical testing under the phase II portion of this application where we will investigate immunogenicity and protective efficacy in nave and pre-immune ferrets and safety and efficacy in a nonhuman primate model that closely resembles humans in their dosing, immune response to DNA vaccination and susceptibility to influenza. If successful, these data will provide Orlance with a strong preclinical IND data package to advance this strategy to phase I human clinical trials. 2